Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae
Authors: Ryan C. Thompson, Nicole W. Simons, Lillian Wilkins, Esther Cheng, Diane Marie Del Valle, Gabriel E. Hoffman, Carlo Cervia, Brian Fennessy, Konstantinos Mouskas, Nancy J. Francoeur, Jessica S. Johnson, Lauren Lepow, Jessica Le Berichel, Christie Chang, Aviva G. Beckmann, Ying-chih Wang, Kai Nie, Nicholas Zaki, Kevin Tuballes, Vanessa Barcessat, Mario A. Cedillo, Dan Yuan, Laura Huckins, Panos Roussos, Thomas U. Marron, Charuta Agashe, Priyal Agrawal, Alara Akyatan, Kasey Alesso-Carra, Eziwoma Alibo, Kelvin Alvarez, Angelo Amabile, Carmen Argmann, Kimberly Argueta, Steven Ascolillo, Rasheed Bailey, Craig Batchelor, Noam D. Beckmann, Priya Begani, Dusan Bogunovic, Swaroop Bose, Cansu Cimen Bozkus, Paloma Bravo, Stacey-Ann Brown, Mark Buckup, Larissa Burka, Sharlene Calorossi, Lena Cambron, Guillermo Carbonell, Gina Carrara, Mario A. Cedillo, Christie Chang, Serena Chang, Steven T. Chen, Jonathan Chien, Mashkura Chowdhury, Jonathan Chung, Phillip H. Comella, Dana Cosgrove, Francesca Cossarini, Liam Cotter, Arpit Dave, Travis Dawson, Bheesham Dayal, Maxime Dhainaut, Rebecca Dornfeld, Katie Dul, Melody Eaton, Nissan Eber, Cordelia Elaiho, Ethan Ellis, Frank Fabris, Jeremiah Faith, Dominique Falci, Susie Feng, Marie Fernandes, Nataly Fishman, Nancy J. Francoeur, Sandeep Gangadharan, Daniel Geanon, Bruce D. Gelb, Benjamin S. Glicksberg, Sacha Gnjatic, Edgar Gonzalez-Kozlova, Joanna Grabowska, Gavin Gyimesi, Maha Hamdani, Diana Handler, Jocelyn Harris, Matthew Hartnett, Sandra Hatem, Manon Herbinet, Elva Herrera, Arielle Hochman, Gabriel E. Hoffman, Jaime Hook, Laila Horta, Etienne Humblin, Suraj Jaladanki, Hajra Jamal, Daniel Jordan, Gurpawan Kang, Neha Karekar, Subha Karim, Geoffrey Kelly, Jong Kim, Seunghee Kim-Schulze, Arvind Kumar, Jose Lacunza, Alona Lansky, Dannielle Lebovitch, Brian Lee, Grace Lee, Gyu Ho Lee, Jacky Lee, John Leech, Michael B. Leventhal, Lora E. Liharska, Katherine Lindblad, Alexandra Livanos, Rosalie Machado, Kent Madrid, Zafar Mahmood, Kelcey Mar, Thomas U. Marron, Glenn Martin, Robert Marvin, Shrisha Maskey, Paul Matthews, Katherine Meckel, Saurabh Mehandru, Miriam Merad, Cynthia Mercedes, Elyze Merzier, Dara Meyer, Gurkan Mollaoglu, Sarah Morris, Konstantinos Mouskas, Emily Moya, Girish Nadkarni, Kai Nie, Marjorie Nisenholtz, George Ofori-Amanfo, Kenan Onel, Merouane Ounadjela, Manishkumar Patel, Vishwendra Patel, Cassandra Pruitt, Adeeb Rahman, Shivani Rathi, Jamie Redes, Ivan Reyes-Torres, Alcina Rodrigues, Alfonso Rodriguez, Vladimir Roudko, Panos Roussos, Evelyn Ruiz, Pearl Scalzo, Eric E. Schadt, Ieisha Scott, Robert Sebra, Sandra Serrano, Hardik Shah, Mark Shervey, Pedro Silva, Laura Sloofman, Melissa Smith, Alessandra Soares Schanoski, Juan Soto, Shwetha Hara Sridhar, Hiyab Stefanos, Meghan Straw, Robert Sweeney, Alexandra Tabachnikova, Collin Teague, Manying Tin, Kevin Tuballes, Scott R. Tyler, Bhaskar Upadhyaya, Akhil Vaid, Verena Van Der Heide, Natalie Vaninov, Konstantinos Vlachos, Daniel Wacker, Laura Walker, Hadley Walsh, Bo Wang, Wenhui Wang, Ying-chih Wang, C. Matthias Wilk, Jessica Wilson, Karen M. Wilson, Hui Xie, Li Xue, Naa-akomaah Yeboah, Nancy Yi, Mahlet Yishak, Sabina Young, Alex Yu, Nicholas Zaki, Nina Zaks, Renyuan Zha, Benjamin S. Glicksberg, Girish Nadkarni, James R. Heath, Edgar Gonzalez-Kozlova, Onur Boyman, Seunghee Kim-Schulze, Robert Sebra, Miriam Merad, Sacha Gnjatic, Eric E. Schadt, Alexander W. Charney, Noam D. Beckmann
Journal: Nature Medicine (2022)

Abstract Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.